This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The purpose of the research study is to determine the safety and effectiveness of high doses of Ursodiol, a ursodeoxycholic acid (UDCA), in the treatment of primary sclerosing cholangitis (PSC). PSC is a chronic liver disease of unknown cause. It is characterized by inflammations and destruction of the hepatic (liver) bile ducts. The disease is slowly progressive and usually leads to cirrhosis, hypertension and liver failure over a 10-15 year period. PSC is one of the most common liver diseases and an important indication for liver transplantation in US adults. The cause of PSC is unknown. In at least 70% of the cases, PSC is associated with inflammatory bowel disease and ulcerative colitis. There are no reports of effective medical therapy for PSC at this time. Traditional treatments for liver disease have not been proven effective in the treatment of PSC. The accumulation of toxic bile acids may be an important mechanism of injury in PSC. Therefore, the rationale for using UDCA in the treatment of PSC includes evidence that it plays an immune modifiying role and replaces the bile acid with a less toxic bile acid (UDCA). In a pilot study of patients with PSC, UDCA improved liver enzymes over 24 months of treatment. Another small trial produced tissue improvements in those treated with UDCA. A larger randomized study showed no significant changes in treatment or death endpoints, however, the dose of UDCA was small. The purpose of this study is to determine if treatment with higher doses of UDCA is effective in the treatment of PSC. Patients will be studies for a minimum of four years of follow-up to determine the long term effects of high doses of UDCA. A subjects visits will be held in the GCRC. Medical and physical examinations, blood measurements, and tissue sample collection will be done for all subjects. In addition, other routine diagnostic tests may be performed. Patients will be required to sign separate consent forms for any additional procedures. All tests done during this study will be done according to the standard of care for treatment of patients with PSC. Data will be used to determine the effectiveness of UDCA in high doses for patients with PSC.